title: Protein pUL128 of human cytomegalovirus is necessary for monocyte infection and blocking of migration.
abstract: We have previously shown that only endotheliotropic strains of human cytomegalovirus (HCMV), such as TB40E, infect monocytes and impair their chemokine-driven migration. The proteins encoded by the UL128-131A region (UL128, UL130, and UL131A) of the HCMV genome, which assemble into a pentameric gH-gL-UL128-UL130-UL131A envelope complex, have been recognized as determinants for HCMV endothelial cell tropism. The genes for these proteins are typically inactivated by mutations in all fibroblast-adapted strains that have lost the diversified tropism of clinical isolates. By using mutant HCMV reconstituted from TB40E-derived bacterial artificial chromosomes (BAC) encoding a wild-type (wt) or mutated form of UL128, we show here that UL128-131A products are essential determinants of infection in monocytes and that pUL128, in particular, can block chemokine-driven motility. The virus BAC4, encoding wt UL128, established infection in monocytes, induced the intracellular retention of several chemokine receptors, and rendered monocytes unresponsive to different chemokines. In contrast, the virus BAC1, encoding a mutated UL128, failed to infect monocytes and to downregulate chemokine receptors. BAC1-exposed monocytes did not express immediate-early (IE) products, retained virions in cytoplasmic vesicles, and exhibited normal chemokine responsiveness. A potential role of second-site mutations in the observed phenotype was excluded by using the revertant viruses BAC1rep and BAC4mut. By incubating noninfected monocytes with soluble recombinant pUL128, we observed both the block of migration and the chemokine receptor internalization. We propose that among the gH-gL-UL128-UL130-UL131A complex subunits, the UL128 protein is the one that triggers monocyte paralysis.
authors.affiliation: Institute of Virology, Ulm University Hospital, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Straschewski
authors.forename: Marco
authors.initials: M
authors.lastname: Patrone
authors.forename: Paul
authors.initials: P
authors.lastname: Walther
authors.forename: Andrea
authors.initials: A
authors.lastname: Gallina
authors.forename: Thomas
authors.initials: T
authors.lastname: Mertens
authors.forename: Giada
authors.initials: G
authors.lastname: Frascaroli
mesh_terms: D002465:Cell Movement; D002478:Cells, Cultured; D018925:Chemokines / Q000276:immunology; D003587:Cytomegalovirus / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology* / Q000821:virology*; D014759:Viral Envelope Proteins / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: D018925:Chemokines; D008562:Membrane Glycoproteins; C532797:UL128 protein, human cytomegalovirus; D014759:Viral Envelope Proteins; D037521:Virulence Factors